Induction and regulation of Trypanosoma brucei VSG-specific antibody responses.

SUMMARY The review addresses how infection with Trypanosoma brucei affects the development, survival and functions ofB lymphocytes in mice. It discusses (1) the contributions of antibodies to trypanosome clearance from the bloodstream,(2) how B lymphocytes, the precursors of antibody producing plasma cells, interact with membrane form variable surfaceglycoprotein (VSG), i.e. with monovalent antigen that is free to diffuse within the lipid bilayer of the trypanosome plasmamembraneandconsequentlycancross-linkBcellantigenspecificreceptorsbyindirectprocessesonlyand(3)theextentandunderlyingcausesofdysregulationofhumoralimmuneresponsesininfectedmice,focusingontheimpactofwildtypeandGPI-PLC x/ trypanosomes on bone marrow and extramedullary B lymphopoiesis, B cell maturation and survival.Key words: T. brucei, antibody clearance, B cell activation, B cell deletion. VSG COAT Trypanosoma brucei inhabits the blood plasma,lymph and interstitial fluids, fully exposed tohumoral immune attack. Its primary defence is acloakofmembrane-boundglycoproteinthatdoesnotelicit production of opsonins or assembly of mem-brane attack complexes in the absence of antibody,and which is subject to antigenic variation. Oneach T. brucei, the surface coat is made up of about10 million identical copies of variable surface glyco-protein (VSG), encoded by a single gene and organ-ized as a more-or-less contiguous array of 5 millionnon-covalent VSG homodimers (Mehlert et al.2002). The expressed VSG gene is selected from alarge archive of silent VSG genes and pseudogenesarranged as sub-telomeric arrays (Marcello andBarry, 2007), and is periodically varied, duringwhich process the trypanosome transitorily has amosaic coat comprised of 2 distinct VSG homo-dimers. VSG genes are expressed in a somewhatorderly manner resulting in recurring waves ofparasitaemia as new variant antigenic types evadeclearancebyon-goingprotectiveantibodyresponses.Irrespective of the VSG gene that is expressed, eachVSG is held in the outer leaflet of the plasma mem-brane by a dimyristoyl glycosyl phosphatidylinositol(GPI) anchor and VSG homodimers are each freeto diffuse in the plane of the plasma membrane,which has important implications for antibody andtrypanosomeinteractionsandfortrypanosomeandBcell interactions as discussed below. In addition, theVSG coat can, under hypo-osmotic and other stressconditions that breach the plasma membrane(Cardoso de Almeida et al. 1984; Rolin et al. 1998),be cleaved from the parasite surface by a GPI-phospholipase C (GPI-PLC). The GPI-PLC is avirulence factor (Webb et al. 1997) that enhancesinflammation, possibly through the action of solubleVSG (sVSG) and remnant GPI (Magez et al. 1998)and, as discussed below, is associated with profounddysregulation of B cell lymphopoiesis, maturationand activation to antibody production.